Tumor Tissue Biobanking and its Role in Translational Medicine: Analysis of Colorectal Cancer Tumors
Erin L. Nacarelli, Master of Science in Histotechnology Program 2014, Drexel University College of Medicine
Methodology:
Abstract:
Translational medicine integrates biomedical research with clinical and diagnostic strategies
to improve health. A resourceful tool of translational medicine in the field of oncology is tumor
tissue biobanking. Tumor tissue biobanking is used for biomedical research for the discovery of
diagnostic and prognostic biomarkers that could provide insight into disease treatment and
prevention. The presented case demonstrates that tumor tissue biobanking serves as a valuable
resource for identifying diagnostic and prognostic biomarkers of colorectal cancer from a series
of colorectal adenocarcinoma tissue specimens. In these tissue specimens, mutated oncogenic
BRAF and microsatellite instability were associated with a poor clinical features and patient
prognosis.
Discussion:
Frozen TTB specimens that were colorectal adenocarcinomas collected between the years
2000 and 2009 were analyzed for mutations
in
the
BRAF
oncogene
from
a
study
population
of
B
475 patients. BRAF mutations were detected using DNA sequencing and polymerase chain
reaction. Genomic instability, a downstream effect of a BRAF mutation, was determined using
microsatellite instability testing. Statistical analysis entail a Fisher exact and X2 tests (5).
Results:
Background:
Tumor tissue biobanking (TTB) plays a major role in translational medicine by serving as a
resource for biomedical research that aids clinicians in patient diagnosis and the development of
therapeutic strategies. Such feats are accomplished by TTB through the discovery of diagnostic
cancer-predictive biomarkers or novel biomarkers that are characteristic of a particular mutational
and pathological status within a tumor tissue sample. This is derived from a spectrum of archived
TTB samples that are associated with a series of data, which constitutes immunohistochemical,
proteomic, microarray expression, sequencing, and genotyping analysis. As anticipated, this
process relies on histotechnology for providing the service of processing, preservation, and
histological analysis of TTB samples. The process of identifying and characterizing a diagnostic
biomarker from tumor tissue for TTB is depicted in the schematic below. This process entails the
acquisition of tumor and control tissue specimens, which can be allocated from TTB, the
discovery of a diagnostic or novel biomarker within the tumor tissue sample using
biotechnological approaches, and validation of the biomarker using repetitive screening within
tumor tissue samples. The study of these TTB specimens will ultimately allow the clinician to
perform surveillance of early stages of the disease and choose a particular therapy that will
prevent the development of malignant cancer and have the best outcome for the patient (1-3). The
broad implication of this process is etiological insight into pathogenesis of cancer and disease
prevention.
TTB can help in understanding the pathogenesis and progression of colorectal cancer. This
disease entails a series of mutations in tumor suppressive genes, such as p53, or oncogenes, such
as KRAS or BRAF, that promote genomic instability and tumorigenesis. It is important that a
clinician may use this mutational status to strategize an effective therapy (3-5).
Table 1. Categorization of patient tumors by
BRAF mutation (Analysis population: 475). Twelve
percent of the study population study contained a
BRAF mutation with a higher trend in females and
older individuals. BRAF mutations were prominent
within tumors of the proximal colon and associated
with a moderate differentiation status and higher
microsatellite instability.
Figure 1. Survival Kaplan-Meier curve comparison
of patients containing BRAF wild-type or mutant
stage I to III colorectal adenocarcinoma tumors
(Analysis population: 322). The patients containing
mutant BRAF-expressing colorectal adenocarcinomas
(RED) contained a statistically significant (p: 0.018)
decrease in percent overall survival. Analysis based
upon a 120 month interval with a median follow-up
analysis of 60 months.
Insight into the clinical effects and patient prognosis were determined based upon TTB of
colorectal adenocarcinoma tissue samples that contained the biomarkers mutated BRAF and
microsatellite instability. Results of these studies demonstrate that TTB colorectal
adenocarcinoma tissue samples that contained mutated BRAF were more prominent in older
individuals and females, exhibit high microsatellite instability, arise particularly in the proximal
colon, and reduce overall survival. Since colorectal cancer may be resistant to chemotherapy
and diminish patient prognosis, this information is absolutely essential in the development of
therapeutics to eliminate mutated BRAF-expressing colorectal tumors in order to improve
survival and prognosis of the patient. In other words, conventional 5-fluorouracil or EGFRbased therapies may not be effective in treating BRAF-expressing colorectal tumors and require
a more specific therapy. This study recognizes the need for specific and personalized therapies
based upon the characterization of a tumor tissue sample. TTB is advantageous for this
approach by the allocation and classification of groups of tumor tissue samples by biomarkers
that could be therapeutically targeted. In addition, this study highlighted the association of
genomic instability, represented by increased microsatellite instability, in mutated BRAFexpressing colorectal adenocarcinoma tissue samples that elicited a worsened patient prognosis
(4-5).
This study provides an example of how TTB is essential in translational medicine by
identifying diagnostic and prognostic biomarkers of a disease, such as colorectal cancer. TTB
permitted the study of colorectal adenocarcinoma tissue samples using the biotechnological
applications of DNA purification, polymerase chain reaction, DNA sequencing, and
microsatellite instability testing. As shown in the schematic below, tumorigenesis drives the
cellular transformation of precursor cells into early and symptomatic cancer. The development
of this process is attributed by the onset or change in levels of biomarkers that are crucial in
diagnostic and prognostic determinations (1-2).
Tumor and control tissue specimens
Sample
Acquisition
Diagnostic or novel biomarker identification using biotechnology
Conclusion:
Biomarker
Discovery
This study demonstrates that a series of biotechnological approaches can be used to
characterize and identify diagnostic and prognostic biomarkers, which can be further
investigated as therapeutic targets, from TTB samples. In the presented case, these biomarkers
identified from TTB colorectal adenocarcinoma samples were mutated BRAF and
microsatellite instability. This study captures the essence of TTB by the characterization of
biomarkers that advance our understanding of the pathogenesis of a disease, such as colorectal
cancer. This gives insight into strategizing, developing, or modifying therapeutics to prevent
the onset and progression of diseases and may serve as a valuable branch of clinical oncology.
Repetitive screening using the identified biomarker within tumor tissue specimens
Biomarker
Validation
Processing and storage of tumor and control tissue specimens in a standardized manner
TTB
Research for
translational medicine
Rationale and Hypothesis:
TTB provides a resource for studying and correlating a mutational status of colorectal
tumors with the clinical features, prognostic outcome, and response of therapy of the patient. The
current case examines the clinical pathology and prognosis from colorectal tumor samples from
TTB that contain a particular mutational status, such as an oncogenic BRAF mutation. TTB in
this case has a role in translational medicine by characterizing BRAF in tumor tissues as a
predictive biomarker for genomic instability, tumorigenesis, and a poor patient prognostic
outcome (5).
Figure 2A. Survival Kaplan-Meier curve
comparison of patients containing BRAF wildtype or mutant microsatellite-stable tumors. The
patients containing microsatellite-stable mutant
BRAF-expressing colorectal adenocarcinomas
(RED) have a non-significant decrease in percent
overall survival. Analysis based upon a 80 month
interval following surgery from removal of
colorectal adenocarcinoma tumor(s).
Figure 2B. Survival Kaplan-Meier curve
comparison of patients containing BRAF wild-type
or mutant microsatellite-unstable tumors. The
patients containing microsatellite-unstable mutant
BRAF-expressing colorectal adenocarcinomas (RED)
have a statistically significant decrease in percent
overall survival. Analysis based upon a 80 month
interval following surgery from removal of colorectal
adenocarcinoma tumor(s).
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